Amination process

ABSTRACT

The present invention provides methodology for carbon-nitrogen bond formation via vinyl or aryl amination. In the process of the invention, an sp 2  hybridized radical is reacted with an azomethine moiety to form pyrrolidine and indole compounds. The methodology provides a facile process for the synthesis of compounds having the pyrrolidine or indole subunit and is especially advantageous for compounds having acid or base labile functional groups and/or is comprised of chiral centers susceptible to acid/base epimerization.

FIELD OF THE INVENTION

[0001] The present invention belongs to the field of synthetic organicchemistry. In particular, it relates to a process for formingcarbon-nitrogen bonds, particularly vinyl-nitrogen bonds andaryl-nitrogen bonds.

BACKGROUND OF THE INVENTION

[0002] The development of methods that effect the formation ofcarbon-nitrogen bonds is a challenge of broad interest due to theprevalence of the aniline subunit within many biologically-activenatural products and medicinal agents (See, e.g., The Alkaloids:Chemistry and Biology, Cordell, G. A., Ed.; Academic: San Diego, 1998,Vol. 50). Significantly, indole alkaloid syntheses frequently commencefrom one of many available aniline or indole derivatives. Although thisstrategy is inherently limited, its popularity is perhaps due to thefact that there are few methods available for forming aryl-nitrogenbonds. Moreover, existing technology generally fails to offer the mildconditions necessary for the highest degree of chemoselectivity.Transition-metal mediated aryl amination generally requires the use of abasic additive to promote the coupling process. Moreover, transitionmetal ligand selection is based upon consideration of the individualelectronic nature of the aromatic halide (or triflate, etc.) and aminecomponents.

[0003] Similar, but fewer, methods are available for vinyl amination.Again, the need for basic and/or nucleophilic addends limits thesubstrate generally of these methodologies. Metal-mediated alkyneamination offers alternative access to the products of vinyl amination(enamines), but functional group tolerance is attenuated further still.Notwithstanding the technological limitations, the products of thesetransformations are valuable both as synthetic intermediates and astargets themselves. Of particular importance is the pyrrolidineheterocyclic class and its oxidized variants (dihydropyrrole andpyrrole). For example, 2-carboxy pyrrolidine is also known as proline,an α-amino acid prevalent in biopeptides. The pyrrolidine backbone isalso found in medicinal agents (i.e., drugs) and numerous classes ofnatural products displaying a range of biological activity.

SUMMARY OF THE INVENTION

[0004] The present invention provides methodology for carbon-nitrogenbond formation via vinyl or aryl amination. In the process of theinvention, an sp² hybridized radical is reacted with an azomethinemoiety to form dihydropyrrole, 2-methylenopyrrolidine, and indolinecompounds. The methodology provides a facile process for the synthesisof compounds having the pyrrolidine or indoline subunit and isespecially advantageous for compounds having acid or base labilefunctional groups and/or is comprised of chiral centers susceptible toacid/base epimerization.

DETAILED DESCRIPTION OF THE INVENTION

[0005] In a first aspect, the present invention provides a process forforming an intramolecular carbon-nitrogen bond which comprises reactingan sp² hybridized carbon radical moiety with an azomethine moiety in thepresence of a hydrogen atom donor, wherein said azomethine moietypossesses at least one radical stabilizing group, and the azomethinecarbon is in the ketone oxidation state or higher. In this regard,suitable radical stabilizing groups are known in the art and include butare not limited to the following: phenyl, vinyl, trifluormethyl,carbonyl, and the like. In a preferred embodiment, the azomethine carbonwill be in the ketone oxidation state and will be bonded by groups suchas hydrocarbyl, substituted hydrocarbyl, aryl, and heteroaryl, providedthat the atom bonded between such groups and the azomethine carbon is acarbon atom.

[0006] As used herein, the term “azomethine” preferably refers to thesubunit having the Formula

[0007] wherein R¹ and R² are as defined herein.

[0008] In this process, the sp² hybridized radical can be formed usingany number of methodologies, including but not limited to preparation ofthe desired carbon radical moiety by photolysis, thermal cleavage, or byhomolytic transmetalation in the presence of a free radical initiatorcompound. In the latter case, the substituted carbon moiety will thuspreferably be substituted by a suitable radical leaving group such as ahalogen atom. The term “free radical intitiator” compound is anycompound which is capable of facilitation of a free radical reaction viaa homolytic mechanism. Examples include azonitrile compounds such as2,2′-azobisisobutyronitrile (AIBN); peroxides; and the like. The carbonradical may also be produced via a prior homolytic reaction, includingbut not limited to a radical addition to an olefin or the thermalcyclization of an ene-diyne moiety.

[0009] Preferred “hydrogen atom donor” compounds include reactants orspecies which can be generated in situ which provide a hydrogen atom.Examples of suitable hydrogen donor compounds include organostannanehydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, selenol, and the like. Examplesof organostannane hydrides include compounds of the Formula (X′)₃Sn—H,wherein X′ is an alkyl group, preferably a C₁-C₆ alkyl group, arylgroup, or a fluorous dervative thereof. Alternatively, such a compoundcan be generated in situ; for example, hexamethylditin can be photolyzedto provide the same tin radical as tri-n-butyl tin hydride plus a freeradical initiator compound. Examples of alkylsilylsilanes includetris(trimethylsilyl)silane, triethylsilane, and the like.

[0010] The process of the invention is particularly well suited for thepreparation of various pyrrolidine compounds. One such compound isproline (or its derivatives):

[0011] Thus, in a second aspect, the present invention provides aprocess for preparing a compound of Formula (2)

[0012] wherein each R is independently selected from the groupconsisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl,heteroaryl, substituted aryl, substituted heteroaryl, heteroatomconnected hydrocarbyl, heteroatom connected substituted hydrocarbyl,heteroatom connected aryl, heteroatom connected heteroaryl, heteroatomconnected substituted aryl, heteroatom connected substituted heteroaryl,a group of the formula —C(O)R¹, a group of the formula —O—R¹, a group ofthe formula —NHR¹, a group of the formula —N(R¹)₂, a group of theformula —Sn(R¹)₃, and a group of the formula —Si(R¹)₃;

[0013] wherein the R¹ and R² groups are independently selected from thegroup consisting of aryl, heteroaryl, hydrocarbyl, substituted aryl,substituted heteroaryl, and substituted hydrocarbyl; provided that saidgroups are bonded via a carbon atom;

[0014] each R³ is independently selected from aryl; heteroaryl;hydrocarbyl; substituted aryl; substituted heteroaryl; substitutedhydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl;heteroatom connected substituted hydrocarbyl; heteroatom connectedheteroaryl; heteroatom connected substituted aryl; halo, preferablyfluoro or chloro, most preferably fluoro; amino; cyano; hydroxy;carboxy; a group of the formula —C(O)O—C₁-C₈ alkyl; a group of theformula —C(O)R¹; a group of the formula —O—R¹; a group of the formula—NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio;and oxo (i.e., an in-line carbonyl group wherein the oxygen is doublybonded with the carbon atom to which R³ is attached, in which case nwill of course be 1); or two R³ groups taken together can form adivalent hydrocarbyl, substituted hydrocarbyl, or be bonded directly toa heteroatom such as oxygen, nitrogen, or sulfur; and n is from 0 to 6;

[0015] which comprises contacting a compound of Formula (1)

[0016] with a free radical initiator in the presence of a hydrogen atomdonor, wherein R, R¹, R², R³, and n are as defined above.

[0017] In a third aspect, there is provided a process for preparingcompounds of the formula

[0018] wherein each R is independently selected from the groupconsisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl,heteroaryl, substituted aryl, substituted heteroaryl, heteroatomconnected hydrocarbyl, heteroatom connected substituted hydrocarbyl,heteroatom connected aryl, heteroatom connected heteroaryl, heteroatomconnected substituted aryl, heteroatom connected substituted heteroaryl,a group of the formula C(O)R¹, a group of the formula —O—R¹, a group ofthe formula —NHR¹, a group of the formula —N(R¹)₂, a group of theformula —Sn(R¹)₃, and a group of the formula —Si(R¹)₃;

[0019] wherein the R¹ and R² groups are independently selected from thegroup consisting of aryl, heteroaryl, hydrocarbyl, substituted aryl,substituted heteroaryl, and substituted hydrocarbyl; provided that saidgroups are bonded via a carbon atom;

[0020] each R³ is independently selected from aryl; heteroaryl;hydrocarbyl; substituted aryl; substituted heteroaryl; substitutedhydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl;heteroatom connected substituted hydrocarbyl; heteroatom connectedheteroaryl; heteroatom connected substituted aryl; amino; halo; cyano;hydroxy; carboxy; a group of the formula —C(O)O—C₁-C₈ alkyl; a group ofthe formula —C(O)R¹; a group of the formula —O—R¹; a group of theformula —NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈alkylthio; and oxo; or two R³ groups taken together can form a divalenthydrocarbyl, substituted hydrocarbyl, or be bonded directly to aheteroatom selected from oxygen, nitrogen, or sulfur; and each n is 0, 1or 2;

[0021] which comprises contacting a compound of the formula

[0022] with a free radical initiator in the presence of a hydrogen atomdonor, wherein Y is a radical leaving group, and X′ is a group selectedfrom C₁-C₆ alkyl, aryl, or a fluorous derivative thereof.

[0023] The compounds of Formula (2) and (2 a) can thus be derivatized toform proline by epoxidation and acid-catalyzed rearrangement to theamino aldehyde. Oxidation and deprotection of the amine providesproline; in this fashion, proline and other proline-subunit containingcompounds may be synthesized using intermediates of Formula (2). Thus,as a fourth aspect of the invention, there is provided the second aspectof the invention as set forth above, further comprising the steps:

[0024] (a) epoxidation, followed by acid catalyzed rearrangement toafford an amino aldehyde, of the formula

[0025]  followed by

[0026] (b) treatment of the resulting aldehyde with a suitable inorganicoxidizing agent,

[0027] (c) followed by deprotection of the nitrogen to provide proline,wherein R¹, R², R³, and n are as defined above.

[0028] In this regard, suitable inorganic oxidizing agents includechromic acid, and suitable methodologies for removal of the R¹ and R²groups (i.e., deprotection of the nitrogen) include conventionalhydrogenation utilizing, for example, H₂, Pd/C, HCO₂H or HCR, in diethylether followed by appropriate workup.

[0029] As an alternative to the alkyne starting material of Formula (1)above, one may utilize the corresponding vinyl halide of Formula (3)

[0030] wherein R, R¹, R², and R³, and n are as defined above, m is zeroor one (in which case, the carbon to which R³ is attached will besubstituted by hydrogen), and X is a halide such as bromo, iodo, orchloro, which provides access to dihydropyrrolidine ring systems havingthe formula

[0031] In the above formula (3), it will be understood that the (R³)_(n)group represents that there may be one, two or no such R³ groups at the4 and 5 positions of the dihydropyrrole ring. It will also be understoodthat either olefin stereoisomer may be utilized in the above methodinsofar as the vinyl radical stereoisomers epimerize rapidly and onlyone leads to the cyclized product.

[0032] Thus, in a fifth aspect, the present invention provides a processfor preparing a compound of the Formula (4)

[0033] wherein each R is independently selected from the groupconsisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl,heteroaryl, substituted aryl, substituted heteroaryl, heteroatomconnected hydrocarbyl, heteroatom connected substituted hydrocarbyl,heteroatom connected aryl, heteroatom connected heteroaryl, heteroatomconnected substituted aryl, heteroatom connected substituted heteroaryl,a group of the formula C(O)R¹, a group of the formula —O—R¹, a group ofthe formula —NHR¹, a group of the formula —N(R¹)₂, a group of theformula —Sn(R¹)₃, and a group of the formula —Si(R¹)₃;

[0034] wherein the R¹ and R² groups are independently selected from thegroup consisting of aryl, heteroaryl, hydrocarbyl, substituted aryl,substituted heteroaryl, and substituted hydrocarbyl; provided that saidgroups are bonded via a carbon atom;

[0035] each R³ is independently selected from aryl; heteroaryl;hydrocarbyl; substituted aryl; substituted heteroaryl; substitutedhydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl;heteroatom connected substituted hydrocarbyl; heteroatom connectedheteroaryl; heteroatom connected substituted aryl; amino; halo; cyano;hydroxy; carboxy; a group of the formula —C(O)O—C₁-C₈ alkyl; a group ofthe formula —C(O)R¹; a group of the formula 4-R¹; a group of the formula—NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio;and oxo; or two R³ groups taken together can form a divalenthydrocarbyl, substituted hydrocarbyl, or be bonded directly to aheteroatom selected from oxygen, nitrogen, or sulfur; m is 0 or 1; andeach n is 0, 1 or 2;

[0036] which comprises contacting a compound of the Formula (3)

[0037] wherein R, R¹, R², and R³, and n are as defined for Formula (4),and X is a halide, with a free radical initiator in the presence of ahydrogen atom donor.

[0038] In the process of this aspect of the invention, the desiredradical may be generated in situ using methodology described above withregard to the first aspect. Thus, in a further embodiment, there isprovided the free radical intermediate of the Formula

[0039] wherein R, R¹, R², R³ and n are as defined above,

[0040] which is useful as an intermediate in the preparation of thecompounds of Formula (2).

[0041] The advantages of the methodology of this invention include thereadily-available amino-alkyne substrates of Formula (1) as depictedabove, as well as the use of radical intermediates and reactionconditions which are pH neutral. Thus, no acid or base addends arenecessary to effect the desired transformation. This feature isespecially advantageous when the desired pyrrolidine compound possessesacid or base labile functional groups and/or is comprised of chiralcenter(s) susceptible to acid/base-catalyzed epimerization. Moreover,there are no electronic restrictions on the substrates, and thus acid-and base-sensitive substrates that are electron rich, electron neutral,or electron deficient may be utilized. This addition of vinyl radicalsto the nitrogen of an azomethine moiety may result in excess of 10:1,preferably 20:1 regioselectivity for the desired carbon-nitrogen bondformation. In contrast to other methodologies for amination, the activenitrogen-containing component in each case is an azomethine, and thepi-bond is its reactive feature (as opposed to a sigma N—H bond).

[0042] In the above Formulae (1) and (2), it will be understood that theindeterminate placement of the R³ group(s) denotes that there may benone or up to 6 of such groups at the carbon atoms α, β, and γ to thenitrogen atom. In this regard, the possible substituents from which R³,as well as R¹ and R² may be selected is not particularly limited, solong as such groups do not contain species which have a deleteriouseffect on the desired reaction or otherwise serve to quench thesp²-hybridized carbon radical prematurely.

[0043] Further examples of starting materials (1) of the presentinvention include (Z) or (E)-vinyl halides. In addition, the process ofthe present invention may be conducted on substrates which are attachedto a solid support via any carbon of the required structural features.In addition, the process of the present invention may be utilized in theconstruction of combinatorial libraries of compounds. Utilizing themethodology of the present invention, entantiomerically enrichedstarting materials may be utilized to prepare enantimerically enrichedfinal products.

[0044] The methodology of the present invention is also useful in thecontext of aryl amination. Thus, in a third aspect, the presentinvention provides a process for forming a carbon-nitrogen bond, whereinsaid carbon is part of an aryl or heteroaryl ring, which comprisesreacting an aryl or heteroaryl radical moiety with an azomethine moietyin the presence of a hydrogen atom donor in an intramolecular reactionto form a fused ring system, wherein said azomethine moiety possesses atleast one radical stabilizing group, and the azomethine carbon is in theketone oxidation state or higher.

[0045] As noted above, the process of the present invention isparticularly well suited for the synthesis of a wide variety ofsubstituted indoline species. In this regard, the phenyl ring in theindoline ring system may possess one or more heteroatoms and may befused to one or more aryl or heteroaryl rings, so long as there is ansp² hybridizable carbon atom alpha to the point of attachment of thetethered azomethine.

[0046] Thus, in a sixth aspect, there is provided a process forpreparing compounds of the formula

[0047] (R⁸)_(n)— (fused aryl and/or heterocyclic ring)

[0048]  wherein each of the groups R⁴, R⁵, and R⁸ are independentlyselected from hydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl;substituted heteroaryl; substituted hydrocarbyl; heteratom connectedaryl; heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, and/or twoR⁸ groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur; and n is from 0 to however many available sitesexist on the ring system, for example, 4 in the case of phenyl and 6 inthe case of napthyl;

[0049]  in addition, two R⁴ groups and/or two R⁵ groups can be takentogether represent oxo;

[0050]  R⁶ and R⁷ are independently selected from aryl, heteroaryl,hydrocarbyl, substituted aryl, substituted heteroaryl, and substitutedhydrocarbyl; provided that said groups are bonded via a carbon atom;

[0051]  and n is from 0 to 4;

[0052] which comprises contacting a compound of the formula

[0053] (R⁸)_(n)— (fused aryl and/or heterocyclic ring)

[0054] wherein said fused aryl and/or heterocyclic ring possesses acarbon alpha to its point of attachment capable of forming an sp²hybridized carbon radical, said carbon substituted by a group Y, whereinY is a radical leaving group;

[0055] with a free radical initiator in the presence of a hydrogen atomdonor.

[0056] In this aspect of the invention, it should be appreciated thatthe groups which are suitable in this process as “fused aryl and/orheterocyclic rings” include aryl and heteroaryl groups as set forthbelow, optionally substituted by one or more R⁸ groups. By way ofexample, if the fused aryl and/or heterocyclic ring is pyridine, onepossible ring structure which can be obtained via this process has theformula:

[0057] Similarly, if the “fused aryl and/or heterocyclic ring” isbenzothiophene, one possible ring system which can be obtained via thisprocess has the formula:

[0058] As noted above, the process of the present invention isespecially useful in the preparation of indoline ring systems. Thus, ina fifth aspect, the present invention provides a process for preparing acompound of Formula (4)

[0059] wherein each of the groups R⁴, R⁵, and R⁸ are independentlyselected from hydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl;substituted heteroaryl; substituted hydrocarbyl; heteratom connectedaryl; heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula —C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, or two R⁸groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur;

[0060] in addition, two R⁴ groups and/or two R⁵ groups can be takentogether represent oxo;

[0061] R⁶ and R⁷ are independently selected from aryl, heteroaryl,hydrocarbyl, substituted aryl, substituted heteroaryl, and substitutedhydrocarbyl; provided that said groups are bonded via a carbon atom;

[0062] and n is from 0 to 4;

[0063] which comprises contacting a compound of Formula (3)

[0064] with a free radical initiator in the presence of a hydrogen atomdonor, wherein Y is a radical leaving group.

[0065] In the process of this aspect of the invention, the desiredradical may be generated in situ using methodology described above withregard to the first aspect. Thus, in a further embodiment, there isprovided the free radical intermediate of the Formula (5)

[0066] which is useful as an intermediate in the preparation of thecompounds of Formula (4).

[0067] In a further preferred embodiment of this aspect, the inventionis useful in the preparation of chiral products, i.e., intermediates andproducts in which the product of the process is enantiomericallyenriched. In this regard, in the case where one of the R⁵ groups iscarboxy, such a chiral synthetic route allows for the preparation ofindoline α-amino acids.

[0068] The advantages of the methodology of this invention include thereadily-available aryl radical precursors (e.g., aryl halides), readilyavailable phenethyl amine derivatives and carbonyl compounds, as well asthe use of radical intermediates and reaction conditions which are pHneutral. Thus, no acid or base addends are necessary to effect thedesired transformation. This feature is especially advantageous when thedesired indole compound possesses acid or base labile functional groupsand/or is comprised of chiral center(s) susceptible toacid/base-catalyzed epimerization. Moreover, there are no electronicrestrictions on the substrates (3), and thus acid- and base-sensitivesubstrates that are electron rich, electron neutral, or electrondeficient may be utilized. This addition of aryl radicals to thenitrogen of an azomethine moiety may result in excess of 10:1, moreoften 20:1 regioselectivity for the desired nitrogen-carbon bondformation. In contrast to other methodologies for amination, the activenitrogen-containing component in each case is an azomethine, and thepi-bond is its reactive feature (as opposed to a sigma N—H bond).

[0069] In the above Formulae (3), (4), and (5), it will be understoodthat the indeterminate placement of the R⁸ groups denotes that there maybe none or up to 4 such groups at the carbon atoms of the phenyl ring.Thus, the process of this aspect of the invention should be recognizedas a general methodology for the synthesis of indole and subsitutedindole species. In this regard, the possible substituents from which R⁸,as well as R⁴, R⁵, R⁶, and R⁷ may be selected is not particularlylimited, so long as such groups do not contain species which have adeleterious effect on the desired reaction or otherwise serve to quenchthe sp²-hybridized carbon radical prematurely. Insofar as such groupsare not limited by acid/base sensitivity or by electonic features, theabove process is useful for making a broad range of compounds containingthe indole subunit. By way of illustration of the robust nature of theprocess of the present invention, one R⁴ group and one R⁵ group could betaken together to form an aziridine ring system.

[0070] Examples of particularly preferred substrates of Formula (3)include homochiral indoline α-amino acids, substituted indolines, etc.

[0071] It is this flexibility which renders the above methodologiesespecially suited for the construction of libraries of compounds,insofar as wide varieties of electron-rich as well as electron-deficientamine and ketone starting materials can be utilized to prepare theazomethine species and in all such cases, provided the above parametersare met, will result in the formation of intramolecular carbon-nitrogenbond formation. Thus, in a further aspect, there is provided a processfor the synthesis of a library of compounds having a proline, indoline,or indole subunit, which comprises application of the methodologyherein.

[0072] In each of the above aspects of the process of the presentinvention, the process may be conducted neat or in a nonparticipatingsolvent such as benzene.

[0073] Also, in each of the above aspects of the invention, the methodsmay be conducted with the substrate attached to a solid support.

[0074] Other desired reaction conditions for the process of the presentinvention are not particularly critical and may in any event be chosenand optimized by one of ordinary skill in the art.

[0075] In this disclosure certain chemical groups or compounds aredescribed by certain terms and symbols. These terms are defined asfollows:

[0076] Symbols ordinarily used to denote elements in the Periodic Tabletake their ordinary meaning, unless otherwise specified. Thus, N, O, S,P, and Si stand for nitrogen, oxygen, sulfur, phosphorus, and silicon,respectively.

[0077] A “hydrocarbyl” group means a monovalent or divalent, linear,branched or cyclic group which contains only carbon and hydrogen atoms.Examples of monovalent hydrocarbyls include the following: C₁-C₂₀ alkyl;C₁-C₂₀ alkyl substituted with one or more groups selected from C₁-C₂₀alkyl, C₃-C₈ cycloalkyl, or aryl; C₃-C₈ cycloalkyl substituted with oneor more groups selected from C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl, or aryl.

[0078] A “substituted hydrocarbyl” refers to a monovalent or divalenthydrocarbyl substituted with one or more heteroatoms. Examples ofmonovalent substituted hydrocarbyls include:—C(O)R¹³ (wherein R¹³ ishydrocarbyl), —C(O)NR¹³ ₂ (wherein R¹³ is hydrocarbyl), 2-hydroxyphenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-fluorophenyl, 2-chlorophenyl,2-trifluoromethylphenyl, 2,6-bis(trifluoromethyl)phenyl,2-(trialkylsiloxy)phenyl, 2(triarylsiloxy)phenyl,2,6-bis(diphenylamino)phenyl, 2,6-bis(phenoxy)phenyl,2-hydroxy-6-phenylphenyl, 2-cyanophenyl, 2-(diphenylamino)phenyl,4-nitrophenyl, 2-nitrophenyl, —CH₂OR¹³ (wherein R¹³ is hydrocarbyl),cyano, —CH₂ NR¹³ ₂ (wherein R¹³ is hydrocarbyl), and —CH₂ OSiR¹³ ⁻³(wherein R¹³ is hydrocarbyl). Also encompassed by the term “substitutedhydrocarbyl” are hydrocarbyl groups having one or more groups selectedfrom amide, imido, carbonyl, carboxy, hydroxy, cyano, nitro, halo,alkoxy, alkoxycarbonyl, carboxamido groups, as well as unsubstituted andsubstituted carboxylic acid ester, unsubstituted and substitutedcarbamoyl, and substituted imino, as such terms are defined herein.Moreover, such substituted hydrocarbyl groups can form aliphatic ringsystems containing one or more heteroatoms and various alkylene linkagessuch as methylene, ethylene, propylene, etc. Examples of such ringsystems include but are not limited to tetrahydrofuran, pyrrolidine,tetrahydropyran, piperidine, and the like.

[0079] Examples of the term “aryl” include a unsubstituted C₆-C₁₄ arylgroup as well as a C₆-C₁₄ aryl substituted with one or more groupsselected from C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl, aryl, amide, imido,carbonyl, carboxy, hydroxy, cyano, nitro, halo, alkoxy, alkoxycarbonyl,carboxamido groups, as well as unsubstituted and substituted carboxylicacid ester, unsubstituted and substituted carbamoyl, and substitutedimino, as such terms are defined herein, and wherein the term “aryl”preferably denotes a phenyl, napthyl, or anthracenyl group.

[0080] A “heteroatom” refers to an atom other than carbon or hydrogen.Preferred heteroatoms include oxygen, nitrogen, phosphorus, sulfur,selenium, arsenic, chlorine, bromine, silicon and fluorine. In thisregard, the terms “heteratom connected aryl”, “heteroatom connectedhydrocarbyl” and like terms indicate that a heteroatom is the point ofattachment for such a group. An example of a heteroatom connectedhydrocarbyl would thus be butanethiol, an example of a heteroatomconnected aryl would be phenoxy, and an example of a heteroatomconnected heteroaryl would be 1-pyrrolyl.

[0081] The term “heteroaryl” as used herein preferably refers toheterocyclic aryl rings having one or more heteroatoms. Preferably, suchheteroaryl groups are stable 5- to 7-membered monocyclic or bicyclic or7- to 10-membered bicyclic heterocyclic rings which are saturatedpartially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S and including any bicyclic group in whichany of the above-defined heterocyclic rings is fused to a benzene ring.The nitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S_and O atoms in the heterocycle is not more than 1.Examples of heterocyclic rings include, but are not limited to,1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,.beta.-carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are notlimited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.

[0082] The terms “substituted aryl” and “substituted heteroaryl” refersto such aryl and heterocyclic rings substituted by one or more halogen,C₁-C₆ alkyl, phenoxy, phenyl, hydroxy, amino, C₁-C₆ alkoxycarbonyl,nitro, C₁-C₆ alkylsulfonyl, carboxy, cyclohexyl, carbamoyl, cyano, C₁-C₆alkylsulfonylamino or C₁-C₆ alkoxy groups, amido, imido, cyano, nitro,C₁-C₆ alkoxy, C₁-C₆ carboxamido groups, as well as unsubstituted andsubstituted carboxylic acid ester, unsubstituted and substitutedcarbamoyl, and substituted imino, as such terms are defined herein.

[0083] The term “alkoxycarbonyl” refers to an alkoxy group bonded to acarbonyl function. In other words, the C₂ alkoxycarbonyl group isethoxycarbonyl. The term “substituted alkoxycarbonyl” refers to a C₁-C₆alkoxycarbonyl group substituted with one or more halogen, phenyl,phenoxy, hydroxy, amino, C₁-C₆ alkoxycarbonyl, carboxy, cyclohexyl,carbamoyl, cyano, C₁-C₆ alkylsulfonylamino, or C₁-C₆ alkoxy groups.

[0084] The terms “alkyl” and “alkylene” as used herein preferably referto C₁-C₁₂ straight or branched chain alkyl and alkylene groups,respectively. The terms “lower alkenyl” and “lower alkynyl” refer toC₃-C₆ alkenyl groups and C₃-C₆ alkynyl groups, respectively.

[0085] The term “unsubstituted and substituted carboxylic acid ester”refers to a C₁-C₈ alkyl, C₃-C₈ cycloalkyl or aryl oxycarbonyl group,preferably containing from 2 to 10 carbon atoms and optionallysubstituted with halogen, C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, aryl, aryloxy,C₁-C₆ alkyl, cyano, C₁-C₆ alkanoyloxy, hydroxy or C₁-C₆ alkoxycarbonyl.

[0086] The term “unsubstituted and substituted carbamoyl” refers to analkyl (or substituted alkyl) amino carbonyl group, preferably containingfrom 2 to 10 carbon atoms.

[0087] The term “substituted imino” refers to an imino group substitutedwith a group selected from hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl oraryl.

[0088] The term “radical leaving group” will be understood by thoseskilled in the art to denote groups such as iodo, bromo, diazoniumsalts, and the like.

[0089] The term “solid support” as used herein preferably refers tosolid supports known in the art of synthetic chemistry as inertmaterials which are attached to a substrate, upon which one or moresynthetic manipulations is to be carried out. This material upon whichthe processes of the invention are performed are referred to as solidsupports, beads and resins. These terms are intended to include: beads,pellets, disks, fibers, gels or particles such as cellulose beads,pore-glass beads, silica gels, polystyrene beads optionally cross-linkedwith divinylbenzene and optionally grafted with polyethylene glycol andoptionally functionalized with amino, hydroxy, carboxy or halo groups,grafted co-poly beads, polyacrylamide beads, latex beads,dimethylacrylamide beads optionally cross-linked with N,N′-bis-acryloylethylene diamine, glass particles coated with hydrophobic polymer, etc.,i.e., material having a rigid or semi-rigid surface and soluble supportssuch as low molecular weight non-cross-linked polystyrene.

[0090] The following examples are set forth merely as illustrations ofthe invention and are not intended to be considered limiting as to thescope thereof.

Experimental Section

[0091] Flame-dried (under vacuum) glassware was used for all non-aqueousreactions. All reagents and solvents were commercial grade and purifiedprior to use when necessary. Diethyl ether (Et₂O), tetrahydrofuran(THF), dichloromethane (CH₂Cl₂), and benzene (C₆H₆) were dried bypassage through a column of activated altumina as described by Grubbs(See Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;Timmers, F. J. Organometallics 1996, 15, 1518-1520.) Benzene wasadditionally passed through a column containing activated Q-5 reactant.Solvents other than benzene were degassed using the freeze-pump-thawmethod when necessary. All additional solvents were dried bydistillation from calcium hydride when necessary. Molecular sieves(spheres, 4 Å) were calcined at 400° C. and stored at room temperaturein an airtight container. AIBN was recrystallized prior to use, andtri-n-butyl tin hydride (^(n)Bu₃SnH) was used as received from Aldrich.Preparations for previously unreported phenethyl amine derivatives usedin this study will be reported later in an Article after optimization.

[0092] Thin layer chromatography (TLC) was performed using glass-backedsilica gel (250μ) plates and flash chromatography utilized 230-400 meshsilica gel from Scientific Adsorbents. Neutral Alumina was used asreceived from Scientific Adsorbents for chromatography of acid-sensitiveintermediates or products. Products were visualized by UV light, iodine,and/or the use of ceric ammonium molybdate, potassium permanganate,ninhydrin, p-anisaldehyde, and potassium iodoplatinate solutions.

[0093] IR spectra were recorded on a Nicolet Avatar 360spectrophotometer. Liquids and oils were analyzed as neat films on asalt plate (transmission), whereas solids were applied to a diamondplate (ATR). Nuclear magnetic resonance spectra (NMR) were acquired oneither a Varian Inova-400 or VXR-400 instrument. Chemical shifts aremeasured relative to tetramethylsilane, as judged by the residualpartially deuterated solvent peak. Mass spectra were obtained using aKratos MS-80 spectrometer using the ionization technique indicated.Combustion analyses were performed on a Perkin-Elmer 2400 Series IICHNS/O Analyzer.

[0094] Ratios of diastereomers and isomeric products were measureddirectly from integration of ¹H NMR absorptions of protons common to thecomponents. Precision was checked by varying the relaxation delay formeasurements on the same compound. Where possible, ratios werecorroborated using GC-mass spectrometry. Peak assignments were made fromauthentic samples in every case. Ratios reported generally represent alower limit defined by multiple runs.

[0095] General Procedure for Ketimine Condensations

[0096] A rapidly stirred benzene solution of the amine (0.5 M), ketone(0.5 M), and 4 Å MS (1:1 w/w) was stirred at 25° C. until completeconversion was achieved, as evidenced by ¹H NMR. The mixture wasfiltered through a pad of Celite and washed with Et₂O or benzene. Thesolvent was removed in vacuo to give the analytically pure ketiminewhich was used immediately.

[0097] The same procedure was used when the benzophenone ketimine wasdesired, except benzophenone imine (Pickard, P. L.; Tolbert, T. L., in“Organic Syntheses”; Wiley: NY, 1973, Collective Vol. 5, pp. 520-2) wasused in place of the ketone. (O'Donnell, M. J.; Polt, R. L. J. Org.Chem. 1982, 47, 2663.)

[0098] General Procedure for Aryl Aminations

[0099] A benzene solution of the ketimine (0.01 M) was warmed to 85° C.in a round-bottomed flask equipped with a condenser. A benzene solution(1 mL) of ^(n)Bu₃SnH (1.1 equiv) and AIBN (0.4 equiv) was loaded into agas-tight syringe and was attached to a syringe pump. The syringe needlewas attached through a septum at the top of the condenser (w/N₂ line) sothat the solution droplets would fall directly into the refluxingbenzene. Following the addition, the reaction mixture was refluxed foran additional period (˜1 h) and cooled to room temperature. At thispoint, an aliquot was removed, concentrated, and component ratios weremeasured by ¹H NMR and/or GC-MS. The solution was treated with NaBH₄(1.1 equiv) and the slurry was stirred 4-5 hours. The mixture wasconcentrated in vacuo, diluted with Et₂O, and washed with water. Theorganic layer was separated, dried (MgSO₄), and concentrated to furnishan oil. Flash chromatography of the crude mixture provided theanalytically pure targeted compounds.

EXAMPLE 1

[0100]

[0101] N-(1-Methylbenzyl)indoline (2a). Following the general procedure,o-bromophenethylamine (46 mg, 231 mmol), acetophenone (27 μL, 231 mmol),and 4 Å MS were stirred in benzene (1 mL) at room temperature for 12 h.Filtering of the mixture through Celite and removal of the solventprovided the ketimine as a>95:5 mixture of stereoisomers. IR (film)3056, 1633 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (m, 2H), 7.57 (d, J=6.9Hz, 2H), 7.40 (t, J=3.1 Hz, 3H), 7.34 (d, J=6.0 Hz, 1H), 7.26 (t, J=6.3Hz, 1H), 7.10 (t, J=6.0 Hz, 1H), 3.79 (dd, J=7.8, 7.8 Hz, 2H), 3.22 (dd,J=7.8, 7.8 Hz, 2H), 2.17 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 166.0,142.0, 140.0, 133.0, 131.7, 129.7, 128.5, 128.1, 127.6, 126.9, 52.2,37.8, 18.1; HRMS (EI: Exact mass calcd for C₁₆H₁₆BrN [M+H]⁺, 302.0544.Found 302.0516.

[0102] A three hour addition of a ^(n)Bu₃SnH (68 μL, 0.25 mmol) and AIBN(15 mg, 93 μmol) solution in benzene (0.7 mL) to a refluxing solution ofthe unpurified ketimine (69.6 mg, 231 μmol) in benzene (23 mL)delivered, after flash chromatography (2% CH₂Cl₂ in hexanes), 44.9 mg(87%) of the desired indoline as a colorless oil. R_(f)=0.62 (30%CH₂Cl₂/hexanes); IR (film) 3046, 1606 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.41 (d, J=7.5 Hz, 2H), 7.29 (t, J=7.2 Hz, 2H), 7.26 (t, J=7.2 Hz, 1H),7.08 (d, J=7.2 Hz, 1H), 7.00 (t, J=7.8 Hz, 1H), 6.6 (t, J=7.2 Hz, 1H),6.36 (d, J=7.8 Hz, 1H), 4.68 (q, J=6.8 Hz, 1H), 3.42 (ddd, J=18.1, 9.1,0 Hz, 1H), 3.35 (ddd, J=15.7, 7.4, 0 Hz, 1H), 2.96 (dd, J=8.5, 8.3 Hz,2H), 2.58 (d, J=6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 151.1 143.0128.7, 127.4, 127.3, 127.1, 124.6, 117.2, 107.5, 54.8, 48.2, 28.5, 16.8;HRMS (EI): Exact mass calcd for C₁₆H₁₇N [M]⁺, 223.1361. Found 223.1366.

EXAMPLE 2

[0103]

[0104] N-(1-Trifluoromethyl)benzyl indoline (2b). Following the generalprocedure, o-bromophenethylamine (852 mg, 4.25 mmol),trifluoroacetophenone (590 μL, 4.21 mmol), and 4 Å MS were stirred intoluene (10 mL) at room temperature for 12 h to provide the ketimine asa >95:5 mixture of stereoisomers. IR (film) 3062, 1669 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.49 (d, J=7.9 Hz, 1H), 7.44 (t J=7.4 Hz, 1H), 7.38 (t,J=7.1 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.10 (t,J=6.0 Hz, 1H), 6.94 (d, J=7.1 Hz, 2H), 3.69 (dd, J=7.1, 7.1 Hz, 2H),3.13 (dd, J=7.1, 7.1 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) ppm 138.4, 133.0,131.7, 130.3, 130.1, 128.8, 128.4, 127.7, 127.5, 124.9, 52.8 36.8; HRMS(EI): Exact mass calcd for C₁₆H₁₃F₃N [M-Br]⁺, 276.1000. Found 276.1003.

[0105] A three hour addition of ^(n)Bu₃SnH (184 μL, 682 μmol) and AIBN(41 mg, 248 μmol) solution in benzene (2.5 mL) to a refluxing solutionof the unpurified ketimine (220 mg, 620 μmol) in benzene (62 μL)delivered, after flash chromatography (5% CH₂Cl₂ in hexanes), 133 mg(77%) of the desired indoline as a colorless oil. R_(f)=0.35 (5%EtOAc/hexanes); IR (film) 3031, 1607 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.40 (m, 5H), 7.11 (t, J=7.9 Hz, 1H), 7.09 (d, J=7.4 Hz, 1H), 6.71 (t,J=7.4 Hz, 1H), 6.62 (d, J=7.9 Hz, 1H), 5.24 (q, J=8.7 Hz, 1H), 3.62 (dd,J=14.2, 8.7, Hz, 1H), 3.19 (dd, J=10.1, 8.9, Hz, 1H), 3.01 (m, 2H); ¹³CNMR (100 MHz, CDCl₃) ppm 150.5, 131.9, 129.3, 129.0, 127.6, 127.5,125.1, 124.7, 118.5, 106.4, 62.0 (q, J=30.5 Hz, 1C), 48.6, 28.5; HRMS(EI): Exact mass calcd for C₁₆H₁₄F₃N [M]⁺, 277.1078. Found 277.1071.

EXAMPLE 3

[0106]

[0107] N-(1-Phenylbenzyl)indoline (2c). Following the general procedure,o-bromophenethylamine (471 mg, 2.35 mmol) and benzophenone imine (426mg, 2.35 mmol) were stirred for 12 h in dichloromethane (4 mL). Removalof the solvent provided the ketimine. IR (film) 3056, 1660, 1623 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=6.8 Hz, 2H), 7.49 (d, J=7.0 Hz,1H), 7.40 (m, J=3.8 Hz, 3H), 7.35 (m, J=7.0 Hz, 3H), 7.24 (t, J=5.8 Hz,1H), 7.19 (d, 6.8 Hz, 1H), 7.05 (t, J=5.8 Hz, 1H), 6.98 (m, J=3.8 Hz,2H), 3.68 (dd, J=7.2, 7.2 Hz, 2H), 3.14 (dd, J=7.4, 7.4, Hz, 2H); ¹³CNMR (100 MHz, CDCl₃) ppm 169.0, 140.0, 139.8, 136.9, 132.9, 131.6,130.1, 128.65, 128.61, 128.4, 128.2, 127.9, 127.4, 125.0, 53.6, 37.9;HRMS (CI): Exact mass calcd for C₂₁H₁₈BrN [M+H]⁺, 364.0701. Found364.0596.

[0108] A three hour addition of a ^(n)Bu₃SnH (70 μL, 254 μmol) and AIBN(5 mg, 9.2 μmol) solution in benzene (1.0 mL) to a refluxing solution ofthe unpurified ketimine in benzene (23 mL) delivered, after flashchromatography (2% CH₂Cl₂ in hexanes), 56.8 mg (86%) of the desiredindoline as a white solid. mp 62-63° C. R_(f)=0.53 (10% EtOAc inhexanes); IR (film) 3025, 1605 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.35 (m,10H), 7.09 (d, J=7.0 Hz, 1H), 6.92 (t, J=7.5 Hz, 1H), 6.64 (t, J=7.0 Hz,1H), 6.20 (d, J=7.5 Hz, 1H), 5.55 (s, 1H), 3.20 (dd, J=8.3, 8.2 Hz, 2H),2.96 (dd, J=8.3, 8.2 Hz, 2H), ¹³C NMR (100 MHz, CDCl₃) ppm 152.1, 141.5,130.5, 128.7, 128.6, 127.4, 127.3, 124.5, 117.7, 66.8, 51.6, 28.5; HRMS(EI): Exact mass calcd for C₂₁H₁₉N [M]⁺, 285.1517. Found 285.1520.

EXAMPLE 4

[0109]

[0110] N-[(1-Methyl)-4-dimethylaminobenzyl]-indoline (2d). According tothe general procedure, o-bromophenethylamine (100 mg, 500 μmol),aceto(p-N,N′-dimethylamino)phenone (81.5 mg, 500 μmol), and 4 Å MS werestirred in benzene (6 mL) at room temperature for 4 h to provide theketimine as a>95:5 mixture of stereoisomers. IR (film) 3050, 1602 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J=9.0 Hz, 2H), 7.46 (dd, J=8.1, 1.1Hz, 1H), 7.25 (dd, J=7.6, 1.5 Hz, 1H), 7.15 (dt, J=7.4, 1.1 Hz, 1H),6.98 (dt, J=6.7, 1.6 Hz, 1H), 6.61 (d, J=9.0 Hz, 2H), 3.65 (t, J=7.4 Hz,2H), 3.10 (t, J=7.4 Hz, 2H), 2.91 (s, 6H), 2.03 (s, 3H); ¹³C NMR (100MHz, CDCl₃) ppm 165.4, 151.6, 143.1, 140.3, 132.9, 131.6, 129.5, 128.0,124.9, 111.7, 51.9, 40.6, 38.01, 15.09; HRMS (EI): Exact mass calcd forC₁₈H₂₁BrN₂ [M]⁺, 334.0888. Found 344.0824.

[0111] A five hour addition of a ^(n)Bu₃SnH (56 μL, 207 μmol) and AIBN(12 mg, 75 μmol) solution in benzene (1 mL) to a refluxing solution ofthe unpurified ketimine (65 mg, 188 μmol) in benzene (18 mL) delivered,after flash chromatography (50% CH₂Cl₂ in hexanes), 45 mg (90%) of thedesired indoline as a crystalline solid, mp 79-82° C.; R_(f)=0.15 (50%CH₂Cl₂/hexanes; IR (film) 2960, 1653 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.28 (t, J=4.2 Hz, 2H), 7.03 (dd, J=17.5, 7.2 Hz, 2H), 6.73 (d, J=8.8Hz, 2H), 6.50 (t, J=7.3 Hz, 1H), 6.44 (d, J=7.9 Hz, 1H), 4.71 (q, J=6.8Hz, 1H), 3.37 (q, J=18.0, 9.2 Hz, 1H), 3.27 (q, J=15.2, 8.4 Hz, 1H),2.95 (s, 6H), 2.93 (t, J=8.0 Hz, 2H), 1.51 (d, J=6.9 Hz, 3H); ¹³C NMR(100 MHz, CDCl₃) ppm 128.2, 127.4, 124.8, 116.8, 112.6, 107.3, 92.1,86.3, 53.9, 47.9, 41.0, 28.4, 16.3; HRMS (EI): Exact mass calcd forC₁₈H₂₂N₂ [M]⁺, 266.1783. Found 266.1774.

EXAMPLE 5

[0112]

[0113] N-[(1-Methyl)-4-dimethylaminobenzyl]-indoline (2e). Following thegeneral procedure, o-bromophenethylamine (429 mg, 2.14 mmol),p-trifluoromethyl acetophenone (404 mg, 2.14 mmol), and 4 Å MS werestirred in benzene (5 mL) at room temperature for 4.5 h to provide theketimine as a 93:7 mixture of stereoisomers. IR (film) 3064, 1636 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.3 Hz,2H), 7.57 (d, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.33-7.21 (m, 1H), 7.10 (t,J=7.7 Hz, 1H), 3.81 (t, J=7.3 Hz, 2H), 3.23 (t, J=7.3 Hz, 2H); ¹³C NMR(100 MHz, CDCl₃) ppm 164.9, 144.6, 139.8, 133.0, 131.7, 128.6, 128.7,129.6, 127.6, 127.2, 125.6, 124.9, 52.3, 37.7, 15.7; HRMS (FAB): Exactmass calcd for C₁₇H₁₆BrF₃N [M+H]⁺, 370.0418. Found 370.0428.

[0114] A three hour addition of a ^(n)Bu₃SnH (91 μL, 337 μmol) and AIBN(20 mg, 123 μmol) solution in benzene (1 mL) to a refluxing solution ofthe unpurified ketimine (113 mg, 307 μmol) in benzene (31 mL) delivered,after flash chromatography (20% CH₂Cl₂ in hexanes), 65 mg (72%) of thedesired indoline as a colorless oil; R_(f)=0.40 (10% EtOAc/hexanes; IR(film) 3048, 1606 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=8.3 Hz,2H), 7.54 (d, J=8.3 Hz, 2H), 7.10 (d, J=6.9 Hz, 1H), 7.01 (t, J=7.5 Hz,1H), 6.65 (t, J=7.1 Hz, 1H), 6.31 (d, J=7.9 Hz, 1H), 4.73 (q, J=6.8 Hz,1H), 3.43 (dd, J=17.9, 8.7 Hz, 1H), 3.37 (dd, J=15.7, 7.4 Hz, 1H), 2.99(t, J=8.3 Hz, 2H), 1.57 (d, J=6.9 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm151.3, 147.5, 130.4, 127.5, 127.4, 125.7, 125.6, 124.8, 54.9, 48.5,28.5, 17.1; HRMS (EI): Exact mass calcd for C₁₇H₁₆F₃N [M]⁺, 291.1235.Found 291.1234.

EXAMPLE 6

[0115]

[0116] N-(1-Trifluoroethyl)-indoline (2f). Following the generalprocedure, o-bromophenethylamine (200 mg, 999 μmol), trifluoroacetone(168 mg, 1.5 mmol), and 4 Å MS were stirred in benzene (5 mL) at roomtemperature for 4 h to provide the ketimine as a>95:5 mixture ofstereoisomers. IR (film) 3059, 1686 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.57(d, J=8.3 Hz, 1H), 7.29-7.22 (m, 2H), 7.13 (dt, J=6.8, 2;4 Hz, 1H), 3.75(t, J=7.3 Hz, 2H), 3.17 (t, J=7.3 Hz, 2H); 1.85 (s, 3H); ¹³C NMR (100MHz, CDCl₃) ppm 157.3 (q, J=33.6 Hz), 138.6, 133.1, 131.8, 127.8, 124.7,121.4, 118.6, 51.4, 36.6, 12.6; HRMS (EI): Exact mass calcd forC₁₁H₁₃BrF₃N [M+H]⁺, 296.0086. Found 296.0088.

[0117] A three hour addition of a ^(n)Bu₃SnH (133 μL, 495 μmol) and AIBN(30 mg, 180 μmol) solution in benzene (1 mL) to a refluxing solution ofthe unpurified ketimine (132 mg, 450 μmol) in benzene (44 mL) provided,after flash chromatography (100% hexanes), 80 mg (83%) of the desiredindoline as a colorless oil. R_(f)=0.15 (hexanes); IR (film) 3050, 1490cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.07 (t, J=7.9 Hz, 2H), 6.65 (t, J=7.3Hz, 1H), 6.44 (d, J=7.8 Hz, 1H), 4.14 (m, 1H), 3.54 (t, J=8.5 Hz, 2H),3.03 (t, J=8.6 Hz, 2H), 1.38 (d, J=7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)ppm 150.3, 129.3, 127.5, 125.0, 118.2, 114.0, 106.3, 52.8 (q, J=28.2Hz), 47.1, 28.5, 10.5; HRMS (EI): Exact mass calcd for C₁₁H₁₂F₃N [M]⁺,215.0922. Found 215.0920.

EXAMPLE 7

[0118]

[0119] N-(iso-Propyl)-indoline (2g). Following the general procedure,o-bromophenethylamine (150 mg, 750 μmol), acetone (44 mg, 750 μmol) and4 Å MS were stirred in benzene (5 mL) at room temperature for 4 h toprovide the ketimine. IR (film) 3055, 1653 cm⁻¹ ¹H NMR (400 MHz, CDCl₃)δ 7.50 (d, J=8.3 Hz, 1H), 7.24-7.18 (m, 2H), 7.04 (td, J=6.9, 2.3 Hz,1H), 3.46 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.7 Hz, 2H), 1.99 (s, 3H), 1.71(s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 168.3, 139.9, 133.0, 131.4, 128.1,127.6, 124.9, 51.6, 37.7, 29.5, 18.6; HRMS (EI) Calcd for C₁₁H₁₅BrN[MH]⁺, 240.0310. Found 240.0389

[0120] A three-hour addition of ^(n)Bu₃SnH (154 μL, 573 μmol) and AIBN(34 mg, 208 μmol) solution in benzene (1 mL) to a refluxing solution ofthe unpurified ketimine (125 mg, 521 μmol) in benzene (50 mL) delivered,after flash chromatography (30% CH₂Cl₂/Hexanes) 0.024 g (30%) of thedesired indoline as a colorless oil. R_(f)=0.1 (30% CH₂Cl₂/Hexanes); IR(film) 3047, 1607 cm¹; ¹H NMR (400 MHz, CDCl₃) δ 7.04 (t, J=6.7 Hz, 2H),6.59 (t, J=7.4 Hz, 1H), 6.42 (d, J=8.1 Hz, 1H), 3.83 (sep, J=6.6 Hz,1H), 3.33 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.3 Hz, 2H), 1.15 (d, J=6.7 Hz,6H); ¹³C NMR (100 MHz, CDCl₃) ppm 151.5, 130.5, 127.5, 124.6, 117.1,107.3, 46.0, 45.7, 28.4, 18.4; HRMS (EI) Exact mass calcd for C₁₁H₁₅N[M]⁺, 161.1204. Found 161.1201.

EXAMPLE 8

[0121]

[0122] N-(1-Methylbenzyl)-3-methylindoline (5a). Following the generalprocedure, 2-(o-bromophenyl)-2-methyl-ethylamine (353 mg, 1.65 mmol),acetophenone (192 μL, 1.64 mmol), and 4 Å MS were stirred in toluene (5mL) at room temperature for 12 h to provide the ketimine as a>95:5mixture of stereoisomers. IR (film) 3057, 1633 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 7.80 (m, 2H), 7.59 (d, J=6.9 Hz, 1H), 7.39 (m, 4H), 7.31 (t,J=6.9 Hz, 1H), 7.08 (t, J=6.1 Hz, 1H), 3.76 (dd, J=10.5, 6.3, Hz, 2H),3.57 (dq, J=13.8, 6.9 Hz, 1H), 2.19 (s, 3H), 1.45 (d, J=6.7 Hz, 3H); ¹³CNMR (100 MHz, CDCl₃) ppm 165.5, 144.9, 141.4, 133.0, 129.6, 128.6,128.4, 128.3, 127.8, 127.6, 126.8, 125.1, 58.1, 39.9, 18.8, 15.7; HRMS(EI): Exact mass calcd for C₁₇H₁₉BrN [M+H]⁺, 316.0701. Found 316.0588.

[0123] A three hour addition of ^(n)Bu₃SnH (84 μL, 314 μmol) and AIBN(18.7 mg, 114 mmol) benzene solution (1 mL) to a refluxing solution ofthe unpurified ketimine (90.3 mg, 286 μmol) in benzene (28 mL) afforded,after flash chromatography (1% ether in hexanes), 58.4 mg (86%) of thedesired indoline as a yellow oil (58:42 mixture of diastereomers).R_(f)=0.6 (10% EtOAc/hexanes); IR (film) 3024, 1605 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.43 (d, J=7.5 Hz, 4H), 7.35 (t, J=7.5 Hz, 6H), 7.03 (d,J=8.0 Hz, 2H), 7.01 (t, J=4.3 Hz, 2H), 6.65 (t, J=7.4 Hz, 2H), 6.36 (d,J=4.3 Hz, 2H), 4.74 (q, J=6.9 Hz, 1H), 4.68 (q, J=6.8 Hz, 1H), 3.62 (dd,J=8.8, 8.8 Hz, 1H), 3.45 (dd, J=8.6, 8.6 Hz, 1H), 3.30 (dq, J=14.6, 7.3Hz, 1H), 2.95 (dd, J=8.8, 8.8 Hz, 2H), 1.57 (d, J=7.0 Hz, 3H), 1.52 (d,J=6.9 Hz, 3H), 1.33 (d, J=6.7 Hz, 3H), 1.27 (d, J=6.8 Hz, 3H); ¹³C NMR(100 MHz, CDCl₃) ppm 151.5, 150.8, 146.4, 143.5, 142.8, 135.4, 135.3,128.68, 128.62, 127.57, 127.53, 127.2, 127.1, 123.5, 123.1, 117.3,117.0, 107.5, 107.2, 56.5, 56.0, 54.9, 54.3, 35.0, 19.9, 18.3, 17.2,16.5; HRMS (EI): Exact mass calcd for C₁₇H₁₉N [M]⁺, 237.1517. Found237.1509.

EXAMPLE 9

[0124]

[0125] N-(1-Phenylbenzyl)-2-methylindoline (1b). Following the generalprocedure, 2-(o-bromophenyl)-1-methyl-ethylamine (50 mg, 234 μmol),benzophenone imine (42 mg, 233 μmol) and 4 Å MS were stirred indichloromethane (2.5 mL) at room temperature for 3 days under argonatmosphere to provide the ketimine as a solid (mp 59-61° C.); IR (film)3057, 1726, 1661 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J=6.9 Hz, 2H),7.45 (d, J=7.4 Hz, 1H), 7.37-7.30 (m, 6H), 7.20-7.14 (m, 2H), 7.03 (dt,J=6.9, 1.4 Hz, 1H), 6.63 (d, J=6.7 Hz, 2H), 3.81 (qd, J=7.8, 6.2, Hz,1H), 3.03 (d, J=4.5 Hz, 1H), 3.01 (d, J=7.1 Hz, 1H), 1.30 (d, J=6.2 Hz,3H); ¹³C NMR (100 MHz, CDCl₃) ppm 167.1, 140.2, 139.4, 137.3, 132.6,130.3, 129.9, 128.6, 128.4, 128.2, 128.1, 127.8, 127.6, 127.1, 125.4,57.4, 44.8, 22.4; HRMS (EI): Exact mass calcd for C₂₂H₂₀BrN [M]⁺,377.0779. Found 377.0630.

[0126] To a refluxing solution of the unpurified ketimine (20 mg, 53μmol) in benzene (9 mL) was added ^(n)Bu₃SnH (15.6 μL, 58.2 μmol),followed by a four-hour addition of AIBN (10.4 mg, 63.5 μmol) dissolvedin benzene (2 mL). After the first 2 h of the reaction, another lot of^(n)Bu₃SnH (15.6 μL, 58.2 μmol) was added to the reaction mixture. Afterthe complete addition of AIBN, the reaction mixture was refluxed for 1h, followed by removal of solvent. Flash chromatography (5% CH₂Cl₂ inhexanes) yielded the desired indoline (13.1 mg, 78%) as a solid (mp58-610C); IR (film) 3060, 1635 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d,J=7.6 Hz, 2H), 7.37-7.26 (m, 8H), 7.04 (d, J=7.1 Hz, 1H), 6.82 (t, J=7.5Hz, 1H), 6.59 (t, J=7.3 Hz, 1H), 5.97 (d, J=7.9 Hz, 1H), 5.65 (s, 1H),3.83 (qd, J=15.0, 6.2 Hz, 1H), 3.25 (dd, J=15.6, 9.0 Hz, 1H), 2.65 (dd,J=15.4, 6.9 Hz, 1H), 1.16 (d, J=6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) ppm138.9, 129.2, 129.0, 128.8, 127.6, 127.2, 124.7, 117.4, 109.4, 100.4,65.5, 52.0, 37.6, 30.1, 21.0; HRMS (EI): Exact mass calcd for C₂₂H₂₁N[M]⁺, 299.1674. Found 299.1682.

EXAMPLE 10

[0127]

[0128] N-(1-Phenylbenzyl)-2,3-trans-dimethylindoline (5c). Following thegeneral procedure, 2-(o-bromophenyl)-1,2-cis-dimethylethylamine (127 mg,562 μmol), benzophenone imine (102 mg, 562 μmol), and 4 Å MS werestirred in dichloromethane (1.5 mL) at room temperature for 7.5 daysunder argon atmosphere to provide the ketimine as an oil; IR (film)3079, 1661 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.48 (m, 3H), 7.44-7.40(m, 3H), 7.347.27 (m, 3H), 7.19 (q, J=7 Hz, 111), 7.18-7.16 (m, 1H),7.00-6.95 (m, 3H), 3.64 (q, J=6.3 Hz, 2H), 3.62 (q, J=6.3 Hz, 1H), 1.44(d, J=6.6 Hz, 3H), 1.41 (d, J=6.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm144.6, 140.6, 137.3, 132.7, 129.8, 129.6, 128.7, 128.4, 128.1, 127.5,62.4, 53.6, 44.8, 19.7, 17.7; HRMS (EI): Exact mass calcd for C₂₃H₂₃BrN[M+H]⁺, 392.1016. Found 392.0913.

[0129] To a refluxing solution of the unpurified ketimine (12.6 mg, 32μmol) in benzene (5.5 mL) was added ^(n) Bu₃SnH (9.5 μL, 35 μmol),followed by a 6 h addition of AIBN (13 mg, 80 μmol) dissolved in benzene(1 mL). After the first 3 h of the reaction, another aliquot of^(n)Bu₃SnH (9.5 mL, 35.4 μmol) was added. After complete addition ofAIBN, the reaction mixture was refluxed for further 1 h followed byevaporation of solvent under vacuum. Flash chromatography (5% CH₂Cl₂ inhexanes) yielded the desired indoline (7.9 mg, 79%) as a gum; IR (film)2958, 1684 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J=7.2 Hz, 2H),7.35-7.26 (m, 8H), 7.02 (d, J=7.2 Hz, H), 6.83 (t, J=7.6 Hz, 1H), 6.61(t, J=7.3 Hz, 1H), 5.99 (d, J=7.9 Hz, 1H), 5.69 (s, 1H), 3.28 (dq,J=6.3, 6.3 Hz, 1H), 2.87 (dq, J=6.9, 6.9 Hz, 1H), 1.27 (d, J=6.4 Hz,3H), 1.19 (d, J=6.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 150.4, 141.1,140.5, 134.3, 128.9, 128.6, 127.4, 123.2, 117.2, 109.2, 66.5, 65.0,43.8, 20.0, 18.8; HRMS (EI): Exact mass calcd for C₂₃H₂₃N [M]⁺,313.1830. Found 313.1838. Relative stereochemistry assigned by NOEexperiments (400 MHz NMR).

EXAMPLE 11

[0130]

[0131] N-(1-Phenylbenzyl)-2,3-cis-dimethylindoline (5d). Following thegeneral procedure, 2-(o-bromophenyl)-1,2-trans-dimethylethylamine (18mg, 79.7 μmol), benzophenone imine (14.4 mg, 79.7 μmol) and 4 Å MS werestirred in dichloromethane (1 mL) at room temperature for 7.5 days underargon atmosphere to provide the ketimine as an oil; IR (film) 3059, 1624cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=7.1 Hz, 2H), 7.62 (dt, J=7.4,1.2 Hz, 2H), 7.51 (t, J=7.7 Hz, 3H), 7.39-7.32 (m, 4H), 7.16 (t, J=7.3Hz, 1H), 7.03 (t, J=7.7 Hz, 1H), 6.80-6.79 (m, 1H), 3.61 (q, J=6.2 Hz,1H), 3.54 (q, J=6.7 Hz, 1H), 1.33 (d, J=7.0 Hz, 3H), 1.13 (d, J=6.3 Hz,3H); ¹³C NMR (100 MHz, CDCl₃) ppm 137.2, 132.9, 132.7, 130.3, 129.9,128.99, 128.5, 128.3, 127.6, 127.3, 61.4, 29.9, 20.6, 16.7; HRMS (EI):Exact mass calcd for C₂₃H₂₂BrN [M+H]⁺, 392.1016. Found 392.1160.

[0132] To a refluxing solution of the unpurified ketimine (5.1 mg, 13μmol) in benzene (3 mL) was added ^(n)Bu₃SnH (4.6 μL, 16.9 μmol),followed by a 6 h addition of AIBN (6.4 mg, 39.0 μmol) dissolved inbenzene (1 mL). After the first 3 h of reaction, another aliquot of^(n)Bu₃SnH (4.6 μL, 16.9 μmol), was added to the reaction mixture. Afterthe complete addition of AIBN, the reaction mixture was refluxed for afurther 2 h, followed by evaporation of solvent under vacuum. Flashchromatography (5% CH₂Cl₂ in hexanes) yielded the desired product (3.4mg, 84%) as a gum; IR (film) 3061, 1605 cm¹; ¹H NMR (400 MHz, CDCl₃) δ7.45 (d, J=6.8 Hz, 2H), 7.40 (d, J=7.2 Hz, 2H), 7.34-7.23 (m, 6H), 7.03(d, J=7.1 Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.63 (t, J=7.3 Hz, 1H), 5.90(d, J=7.8 Hz, 1H), 5.51 (s, 1H), 3.78 (dq, J=7.5, 6.4 Hz, 1H), 3.38 (dq,J=7.3, 7.3 Hz, 1H), 1.22 (d, J=7.1 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H); ¹³CNMR (100 MHz, CDCl₃) ppm 150.0, 142.4, 141.2, 135.5, 128.9, 128.7,128.6, 127.9, 127.4, 127.2, 126.9, 123.1, 117.5, 109.9, 65.4, 62.4,39.1, 13.6, 12.6; HRMS (FAB): Exact mass calcd for C₂₃H₂₃N [M]⁺,313.1830. Found 313.1839.

[0133] Relative stereochemistry determined by NOE experiments (400 MHzNMR).

EXAMPLE 12

[0134]

[0135] N-(1-Methylbenzyl)-3,3-dimethylindoline (5e). According to thegeneral procedure, 2-(o-bromophenyl)-2,2-dimethyl ethylamine (733 mg,3.21 μmol), acetophenone (370 μL, 3.18 μmol), and 4 Å MS were stirred intoluene (25 mL) at room temperature for 12 h to provide the ketimine asa>95:5 mixture of stereoisomers, IR (film) 3058, 1635 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.66 (m, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.50 (d, J=9.8 Hz,1H), 7.30 (t, J=1.8 Hz, 3H); 7.23 (t, J=4.3 Hz, 1H), 7.0 (t, J=9.4 Hz,1H), 3.98 (s, 2H), 2.20 (s, 3H), 1.64 (s, 6H); ¹³C NMR (100 MHz, CDCl₃)ppm 164.3, 146.3, 141.5, 135.8, 130.0, 129.4, 128.2, 127.7, 127.3,126.8, 122.8, 60.4, 41.8, 26.8, 26.5, 15.6; HRMS (CI): Exact mass calcdfor C₁₈H₂₁BrN, [M+H]⁺, 330.0857. Found 330.0818.

[0136] A three hour addition of ^(n)Bu₃SnH (72.0 μL, 267 μmol) and AIBN16 mg, 97 μmol) benzene solution (1.0 mL) to a refluxing solution of theunpurified ketimine (80.2 mg, 243 μmol) in benzene (24 mL) furnished,after flash chromatography (1% Et₂O in hexanes) 48.8 mg (80%) of thedesired indoline as a colorless oil. R_(f)=0.63 (10% EtOAc/hexanes); IR(film) 3024, 1604 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J=7.4 Hz,2H), 7.35 (t, J=7.2 Hz, 2H), 7.26 (d, J=7.3 Hz, 1H), 7.01 (t, J=7.2 Hz,1H), 7.01 (t, J=7.2 Hz, 1H), 6.66 (t, J=8.1 Hz, 1H), 6.35 (d, J=8.1 Hz,1H), 4.73 (q, J=6.9 Hz, 1H), 3.18 (d, J=8.3 Hz, 1H), 3.08 (d, J=8.3 Hz,1H), 1.54 (d, J=6.9 Hz, 3H), 1.33 (s, 3H), 1.27 (s, 3H); ¹³C NMR (100MHz, CDCl₃) ppm 150.1, 143.4, 139.2, 128.6, 127.5, 127.2, 127.1, 121.8,117.2, 107.3, 62.6, 54.3, 39.9, 28.3, 27.4, 17.0; HRMS (EI): Exact masscalcd for C₁₈H₂₁N [M]⁺, 251.1674. Found 251.1672.

EXAMPLE 13

[0137]

[0138] N-(1-Phenylbenzyl)-3-methoxyindoline (5f).2-(o-Bromophenyl)-2-methoxyethylamine (43.4 mg, 189 μmol), benzophenoneimine (32 μL, 189 μmol), and 4 Å MS were stirred in CH₂Cl₂ at roomtemperature for 7 h. Removal of the solvent provided the ketimine as acolorless oil. IR (film) 3058, 1626 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.63(d, J=8.3 Hz, 2H), 7.52 (dd, J=8.1, 2.2 Hz, 1H), 7.45-7.28 (m, 8H), 7.13(dt, J=9.3, 1.6 Hz, 1H), 7.07 (dd, J=7.5, 2.4 Hz, 2H), 5.05 (dd, J=6.7,4.5 Hz, 1H), 3.71 (dd, J=14.0, 4.4 Hz, 1H), 3.64 (dd, J=14.0, 6.9 Hz,1H), 3.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 169.8, 140.1 (2C),137.0, 132.82, 130.2, 129.1, 128.8 (2C), 128.65, 128.6, 128.54, 128.2,127.7, 123.8, 82.8, 59.2, 57.6; HRMS (EI): Exact mass calcd forC₂₂H₂₁BrNO [M+H]⁺, 394.0808. Found 394.0795.

[0139] A three hour addition of ^(n)Bu₃SnH (38 μL, 143 μmol) and AIBN(8.5 mg, 52 μmol) in benzene (1 mL) to a refluxing solution of theunpurified ketimine (51.2 mg, 130 μmol) in benzene (13 mL) afforded,after flash chromatography on basic alumina (10% CH₂Cl₂ in hexanes), 29mg (70%) of the desired indoline as a colorless oil. R_(f)=0.15 (10%CH₂Cl₂/hexanes); IR (film) 3059, 1608 cm¹; ¹H NMR (400 MHz, CDCl₃) δ7.40-7.26 (m, 11H), 7.10 (dt, J=8.1, 1.2 Hz, 1H), 6.71 (t, J=7.25 Hz,1H), 6.34 (d, J=7.9 Hz, 1H), 5.70 (s, 1H), 4.79 (dd, J=6.7, 2.6 Hz, 1H),3.35 (s, 3H), 3.33 (dd, J=11.3, 2.7 Hz, 1H), 3.27 (dd, J=11.2, 6.7 Hz,1H); ¹³C NMR (100 MHz, CDCl₃) ppm 140.7, 130.1, 129.2, 128.8, 128.7,128.4, 128.2, 127.7, 127.5, 126.1 78.9, 65.7, 56.4, 55.4; HRMS (EI):Exact mass calcd for C₂₂H₂₁NO [M]⁺, 315.1623. Found 315.1623.

EXAMPLE 14

[0140]

[0141] N-(1-Methylbenzyl)-5,6-dimethoxy indoline (8a). Following thegeneral procedure, (2-bromo-4,5-dimethoxyphenyl)ethylamine (1.95 g, 7.5mmol), acetophenone (0.87 mL, 7.5 mmol), and 4 Å MS were stirred intoluene (10 mL) at room temperature for 12 h to provide the ketimine asa>95:5 mixture of stereoisomers. IR (film) 3055, 1633 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.77 (m, 2H), 7.38 (m, 3H), 7.03 (s, 1H), 6.83 (s, 1H),3.87 (s, 3H), 3.79 (s, 3H), 3.77 (dd, J=7.2, 7.2 Hz, 2H), 3.14 (dd,J=7.4, 7.4 Hz, 2H), 2.11 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 166.1,158.0, 148.3, 148.2, 141.4, 131.9, 129.7, 128.5, 126.7, 115.6, 114.4,56.3, 56.1, 52.2, 37.3, 15.6; HRMS (CI): Exact mass calcd forC₁₈H₂₁BrNO₂ [MH]⁺, 362.0756. Found 362.0747.

[0142] A three-hour addition of ^(n)Bu₃SnH (120 μL), 448 μmol) and AIBM(26.7 mg, 163 μmol) solution in benzene (1.1 mL) to a refluxing solutionof the unpurified ketimine (148 mg, 408 μmol) in benzene (41 μL)afforded, after flash chromatography (15% EtOAc in hexanes), 95.6 mg(83%) of the desired indoline as a yellow oil. R_(f)=0.27 (20%EtOAc/hexanes); IR (film) 3059, 1614 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.45 (d, J=7.6 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H),6.75 (s, 1H), 6.00 (s, 1H), 4.57 (q, J=6.8 Hz, 1H), 3.80 (s, 3H), 3.70(s, 3H), 3.34 (dd, J=16.2, 7.3 Hz, 2H), 2.88 (dd, 7.9, 7.9 Hz, 2H), 1.53(d, J=7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) ppm 149.0, 146.5, 143.6,141.5, 128.6, 127.3, 127.1, 121.3, 111.2, 95.4, 57.6, 49.6, 28.4, 17.5;HRMS (EI): Exact mass calcd for C₁₈H₂₁NO₂ [M]⁺, 283.1572. Found283.1578.

EXAMPLE 15

[0143]

[0144] N-(1-Trifluoromethyl(benzyl)-5,6-dimethoxy indoline (8b).Following the general procedure,(2-bromo-4,5-dimethoxy-phenyl)ethylamine (2.05 g, 7.88 mmol),trifluoroacetophenone (1.1 mL, 7.88 mmol), and 4 Å MS were stirred intoluene (30 mL) at room temperature for 12 h to give the ketimine asa>95:5 mixture of stereoisomers. IR (film) 3061, 1669 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.43 (t, J=7.2 Hz, 1H), 7.38 (t, J=7.5 Hz, 2H), 6.95 (s,1H), 6.91 (d, J=7.1 Hz, 2H), 6.70 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H),3.67 (dd, J=8.2, 6.8 Hz, 2H), 3.05 (dd, J=6.7, 6.7 Hz, 2H); ¹³C NMR (100MHz, CDCl₃) ppm 159.5, 159.2, 148.5, 148.3, 130.4, 130.2, 130.1, 128.8,128.5, 127.7, 121.1, 118.4, 115.5, 114.5, 114.2, 56.4, 56.1, 52.9, 36.4;HRMS (EI): Exact mass calcd for C₁₈H₁₇BrF₃NO₂ [M]⁺, 415.0395. Found415.0414.

[0145] A three-hour addition of ^(n)Bu₃SnH (110 μL, 412 μmol) and AIBN(25 mg, 150 μmol) solution in benzene 1.0 mL) to a refluxing solution ofthe unpurified ketimine (156 mg, 375 μmol) in benzene (37 mL) provided,after flash chromatography (10% EtOAc in hexanes), 113 μg (89%) of thedesired indoline as a yellow oil. R_(f)=0.37 (20% EtOAc/hexanes); IR(film) 2939, 1615 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.39 (m, 5H), 6.74 (s,1H), 6.27 (s, 1H), 5.11 (q, J=8.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H),3.57 (dd, J=15.1, 8.8 Hz, 1H), 3.15 (dd, J=18.4, 9.3 Hz, 1H), 2.89 (m,2H); ¹³C NMR (100 MHz, CDCl₃) ppm 149.3, 144.9, 142.4, 132.0, 128.9,120.2, 111.2, 94.2, 62.8 (q, J=29.7 Hz, 1C), 57.4, 56.6, 49.6, 28.5;HRMS (EI): Exact mass calcd for C₁₈H₁₈F₃NO₂ [M]⁺, 337.1290. Found337.1280.

EXAMPLE 16

[0146] N-(1-Phenylbenzyl)-5,6-dimethoxy indoline (8c). Following thegeneral procedure, (2-bromo-4,5-dimethoxyphenyl)ethyl amine (343 mg,1.32 mmol) and benzophenone imine (239 mg, 1.32 mmol) were stirred atroom temperature in CH₂Cl₂ (3 mL) for 12 h to give the ketimine. IR(film) 3056, 1623 cm¹; ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=7.0 Hz, 2H),7.40 (dd, J=6.2, 3.4 Hz, 3H), 7.36 (t, J=7.6 Hz, 3H), 6.95 (s, 1H), 6.94(d, J=2.3 Hz, 2H), 6.73 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.67 (dd,J=7.0, 7.0 Hz, 2H), 3.07 (dd, J 7.2, 7.2 Hz, 2H); ¹³C NMR (100 MHz,CDCl₃) ppm 168.9, 148.2, 139.9, 136.8, 131.8, 128.5, 128.4, 128.3,127.9, 115.5, 114.5, 114.2, 56.3, 56.1, 53.8, 37.4; HRMS (CI): Exactmass calcd for C₂₃H₂₃BrNO₂ [M+H]⁺, 424.0912. Found 424.0910.

[0147] A three-hour addition of ^(n)Bu₃SnH (75 μL, 278 μmol) and AIBN(17 mg, 101 μmol) solution in benzene (1.0 mL) to refluxing solution ofthe unpurified ketimine (107 mg, 252 μmol) in benzene (25 mL) provided,after flash chromatography (5% EtOAc in hexanes), 46 mg (64%) of thedesired indoline as a white solid. mp 105-106° C.; R_(f)=0.20 (10%EtOAc/hexanes); IR (film) 2931, 1597 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.45 (d, J=7.1 Hz, 4H), 7.35 (t, J=7.1 Hz, 4H), 7.27 (t, J=4.7 Hz, 2H),6.75 (s, 1H), 5.79 (s, 1H), 5.33 (s, 1H), 3.80 (s, 3H), 3.51 (s, 3H),3.16 (dd, J=8.3, 8.3, Hz, 2H), 2.87 (dd, J=8.1, 8.1, Hz, 2H); ¹³C NMR(100 MHZ, CDCL₃) ppm 148.4, 146.9, 142.1, 141.8, 128.7, 128.5, 127.4,121.7, 110.4, 96.5, 69.3, 57.3, 55.9, 53.6, 28.5; HRMS (CI): Exact masscalcd for C₂₃H₂₃NO₂ [M]⁺, 345.1729. Found 345.1713.

EXAMPLE 17

[0148]

[0149] N-(1-Phenylbenzyl)-6-azaindoline (8d). 2-Bromo-3-(2-aminoethyl)pyridine (104 mg, 517 μmol) and benzophenone imine (94 mg, 517 μmol)were stirred in CH₂Cl₂ at room temperature for 8 h to provide theketimine. IR (film) 3056, 1622 cm¹; ¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd,J=4.7, 0.9 Hz, 1H), 7.56 (t, J=7.8 Hz, 3H), 7.43-7.40 (m, 3H), 7.37 (d,J=6.6 Hz, 1H), 7.32 (t, J=7.9 Hz, 2H), 7.16 (dd, J=7.4, 5.2 Hz, 1H);6.96 (t, J=3.4 Hz, 2H), 3.69 (t, J=6.9 Hz, 2H), 3.10 (t, J=6.9 Hz, 2H);¹³C NMR (100 MHz, CDCl₃) ppm 169.2, 158.1, 147.7, 144.5, 139.5, 137.0,136.5, 130.0, 128.5, 128.4, 128.3, 127.5, 122.6, 52.4, 36.8; HRMS (EI):Exact mass calcd for C₂₀H₁₇BrN₂ [M]⁺, 364.0575. Found 364.0587.

[0150] A two-hour addition of ^(n)Bu₃SnH (58 μL, 214 μmol) and AIBN (39mg, 235 μmol) solution in benzene (2 mL) to a refluxing solution of theunpurified ketimine (36 mg, 98 mmol) in benzene (10 mL) delivered, afterflash chromatography (5% EtOAc/Hexanes), 14 mg (50%) of the desiredindoline as an orange crystalline solid. mp 101° C.; R_(f)=0.1 (5%EtOAc/Hexanes); IR (film) 3058, 1611 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.87 (d, J=5.2 Hz, 1H), 7.34-7.26 (m, 10H), 7.17 (d, J=7.0 Hz, 1H), 6.81(s, 1H), 6.42 (t, J=6.5 Hz, 1H), 3.34 (t, J=8.5 Hz, 2H), 2.97 (t, J=8.5Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) ppm 162.8, 146.1, 140.2, 131.2, 122.8,129.1, 128.5, 127.4, 112.4, 60.0, 45.6, 25.9; HRMS (EI) Calcd forC₂₀H₁₈N₂ [M]⁺, 286.1470. Found 286.1468.

EXAMPLE 33

[0151] General Example for Vinyl Amination

[0152] 4-Pentyn-1-amine (0.59 g) was dissolved in 8 mL of dry benzene,and 4A molecular sieves (˜4 g) were added to the solution. The mixturewas stirred at room temperature and 0.78 mL of acetophenone was addeddropwise. The mixture was allowed to stirr for at least 6 hours. Thereaction mixture was filtered through a plug of celite, and themolecular sieves were washed with ether. The solvent was washed in vacuoto afford the 4-pentyn-1-imine in 94% yield.

[0153] The imine (0.1709 g) was dissolved in 46 mL benzene and heated toreflux at 85°. AIBN (0.0224 g, 0.2 eq.) and tri-n-butyltin hydride (0.25mL, eq.) were dissolved in a minimal amount of benzene (˜1 mL) and drawninto syringe. This solution was added dropwise over 3 hours via syringepump to the refluxing imine solution. After complete addition of AIBNand tri-n-butyltin hydride, the mixture was allowed to reflux for anadditional 3 hours. Once the reaction had gone to completion, thereaction mixture was cooled to room temperature and the solvent wasremoved in vacuo.

We claim:
 1. A process for forming an intramolecular carbon-nitrogenbond which comprises reacting an sp² hybridized carbon radical moietywith an azomethine moiety in the presence of a hydrogen atom donor,wherein said azomethine moiety possesses at least one radicalstabilizing group, and the azomethine carbon is in the ketone oxidationstate or higher.
 2. The process of claim 1, wherein the azomethinecarbon is in the ketone oxidation state.
 3. The process of claim 1,wherein the azomethine carbon is bonded by groups selected fromhydrocarbyl, substituted hydrocarbyl, aryl, and heteroaryl, providedthat the atom bonded between such groups and the azomethine carbon willbe other than a heteroatom.
 4. The process of claim 1, wherein theazomethine carbon is bonded to at least one group selected from thegroup consisting of phenyl, vinyl, trifluormethyl, and carbonyl.
 5. Theprocess of claim 1, wherein the hydrogen atom donor is selected fromorganostannane hydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, and selenols.
 6. The process ofclaim 5, wherein the organostannane is a compound of the Formula(X′)₃Sn—H, wherein X′ is a group selected from C₁-C₆ alkyl, aryl, or afluorous derivative therof.
 7. The process of claim 6, wherein thecompound of the Formula a (X′)₃Sn—H is tri-n-butyltin hydride.
 8. Theprocess of claim 1, wherein said process is applied to an array ofcompounds comprising an azomethine moiety to provide a library ofcompounds comprising a pyrrolidine and/or indoline subunit.
 9. Theprocess of claim 1, wherein said process is conducted on a solidsupport.
 10. A process for preparing a compound of Formula (2)

wherein each R is independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, heteroaryl,substituted aryl, substituted heteroaryl, heteroatom connectedhydrocarbyl, heteroatom connected substituted hydrocarbyl, heteroatomconnected aryl, heteroatom connected heteroaryl, heteroatom connectedsubstituted aryl, heteroatom connected substituted heteroaryl, a groupof the formula —C(O)R¹, a group of the formula —O—R¹, a group of theformula —NHR¹, a group of the formula —N(R¹)₂, a group of the formula—Sn(R¹)₃, and a group of the formula —Si(R¹)₃; wherein the R¹ and R²groups are independently selected from the group consisting of aryl,heteroaryl, hydrocarbyl, substituted aryl, substituted heteroaryl, andsubstituted hydrocarbyl; provided that said groups are bonded via acarbon atom; each R³ is independently selected from aryl; heteroaryl;hydrocarbyl; substituted aryl; substituted heteroaryl; substitutedhydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl;heteroatom connected substituted hydrocarbyl; heteroatom connectedheteroaryl; heteroatom connected substituted aryl; halo; amino; cyano;hydroxy; carboxy; a group of the formula —C(O)O—C₁-C₈ alkyl; a group ofthe formula C(O)R¹; a group of the formula —O—R¹; a group of the formula—NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio;and oxo; or two R³ groups taken together can form a divalenthydrocarbyl, substituted hydrocarbyl, or be bonded directly to aheteroatom selected from oxygen, nitrogen, or sulfur; and n is from 0 to6; which comprises contacting a compound of Formula (1)

with a free radical initiator in the presence of a hydrogen atom donor,wherein R, R¹, R², R³, and n are as defined above.
 18. The process ofclaim 17, wherein the hydrogen atom donor is selected fromorganostannane hydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, and selenols.
 19. The processof claim 18, wherein the organostannane is a compound of the Formula(X′)₃Sn—H, wherein X′ is a group selected from C₁-C₆ alkyl, aryl, or afluorous derivative thereof.
 20. The process of claim 17, wherein thecompound of the Formula (X′)₃Sn—H is tri-n-butyltin hydride.
 21. Theprocess of claim 17, wherein the free radical initiator is selected fromthe group consisting of azonitriles and peroxides.
 22. The process ofclaim 21, wherein the free radical initiator is2,2′-azobisisobutyronitrile.
 23. The process of claim 17, wherein thecompound of Formula (1) is attached to a solid support.
 24. A processfor preparing compounds of the formula

wherein each R is independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, heteroaryl,substituted aryl, substituted heteroaryl, heteroatom connectedhydrocarbyl, heteroatom connected substituted hydrocarbyl, heteroatomconnected aryl, heteroatom connected heteroaryl, heteroatom connectedsubstituted aryl, heteroatom connected substituted heteroaryl, a groupof the formula —C(O)R¹, a group of the formula —O—R¹, a group of theformula —NHR¹, a group of the formula —N(R¹)₂, a group of the formula—Sn(R¹)₃, and a group of the formula —Si(R¹)₃; wherein the R¹ and R²groups are independently selected from the group consisting of aryl,heteroaryl, hydrocarbyl, substituted aryl, substituted heteroaryl, andsubstituted hydrocarbyl; provided that said groups are bonded via acarbon atom; each R³ is independently selected from aryl; heteroaryl;hydrocarbyl; substituted aryl; substituted heteroaryl; substitutedhydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl;heteroatom connected substituted hydrocarbyl; heteroatom connectedheteroaryl; heteroatom connected substituted aryl; amino; halo; cyano;hydroxy; carboxy; a group of the formula —C(O)O—C₁-C₈ alkyl; a group ofthe formula —C(O)R¹; a group of the formula —O—R¹; a group of theformula —NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈alkylthio; and oxo; or two R³ groups taken together can form a divalenthydrocarbyl, substituted hydrocarbyl, or be bonded directly to aheteroatom selected from oxygen, nitrogen, or sulfur; and n is 0, 1 or2; which comprises contacting a compound of the formula

with a free radical initiator in the presence of a hydrogen atom donor,wherein Y is a radical leaving group, and X′ is selected from C₁-C₆alkyl, aryl, or a fluorous derivative thereof.
 25. The process of claim24, wherein the hydrogen atom donor is selected from organostannanehydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, and selenols.
 26. The processof claim 25, wherein the organostannane is a compound of the Formula(X′)₃Sn—H, wherein X′ is a group selected from C₁-C₆ alkyl, aryl, or afluorous derivative thereof.
 27. The process of claim 25, wherein thecompound of the Formula (X′)₃Sn—H is tri-n-butyltin hydride.
 28. Theprocess of claim 25, wherein the free radical initiator is selected fromthe group consisting of azonitriles and peroxides.
 29. The process ofclaim 28, wherein the free radical initiator is2,2′-azobisisobutyronitrile.
 30. The process of claim 24, wherein thecompound of Formula (1) is attached to a solid support.
 31. The processof claim 17 or 24, further comprising the steps: a) epoxidation,followed by acid catalyzed rearrangement to afford an amino aldehyde, ofthe formula

 followed by (b) treatment of the resulting aldehyde with a suitableinorganic oxidizing agent, (c) followed by deprotection of the nitrogento provide proline.
 32. A process for preparing a compound of theFormula (4)

wherein each R is independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, heteroaryl,substituted aryl, substituted heteroaryl, heteroatom connectedhydrocarbyl, heteroatom connected substituted hydrocarbyl, heteroatomconnected aryl, heteroatom connected heteroaryl, heteroatom connectedsubstituted aryl, heteroatom connected substituted heteroaryl, a groupof the formula (O)R¹, a group of the formula —R¹, a group of the formula—NHR¹, a group of the formula —N(R¹)₂, a group of the formula —Sn(R¹)₃,and a group of the formula —Si(R¹)₃; wherein the R¹ and R² groups areindependently selected from the group consisting of aryl, heteroaryl,hydrocarbyl, substituted aryl, substituted heteroaryl, and substitutedhydrocarbyl; provided that said groups are bonded via a carbon atom;each R³ is independently selected from aryl; heteroaryl; hydrocarbyl;substituted aryl; substituted heteroaryl; substituted hydrocarbyl;heteratom connected aryl; heteroatom connected hydrocarbyl; heteroatomconnected substituted hydrocarbyl; heteroatom connected heteroaryl;heteroatom connected substituted aryl; amino; halo; cyano; hydroxy;carboxy; a group of the formula —C(O)O—C₁-C₈ alkyl; a group of theformula —C(O)R¹; a group of the formula —O—R¹; a group of the formula—NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio;and oxo; or two R³ groups taken together can form a divalenthydrocarbyl, substituted hydrocarbyl, or be bonded directly to aheteroatom selected from oxygen, nitrogen, or sulfur; m is 0 or 1; andeach n is 0, 1 or 2; which comprises contacting a compound of theFormula (3)

wherein R, R¹, R², and R³, and n are as defined for Formula (4), and Xis a halide, with a free radical initiator in the presence of a hydrogenatom donor.
 33. The process of claim 32, wherein the hydrogen atom donoris selected from organostannane hydrides, organosilyl silanes,organogermanium hydrides, 1,4-cyclohexadiene, γ-terpinene, thiols, andselenols.
 34. The process of claim 32, wherein the organostannane is acompound of the Formula (X′)₃Sn—H, wherein X′ is a group selected fromC₁-C₆ alkyl, aryl, or a fluorous derivative thereof.
 35. The process ofclaim 32, wherein the compound of the Formula (X′)₃Sn—H istri-n-butyltin hydride.
 36. The process of claim 32, wherein the freeradical initiator is selected from the group consisting of azonitrilesand peroxides.
 37. The process of claim 32, wherein the free radicalinitiator is 2,2′-azobisisobutyronitrile.
 38. The process of claim 32,wherein the compound of Formula (3) is attached to a solid support. 39.A free radical intermediate of the Formula

wherein each R is independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, heteroaryl,substituted aryl, substituted heteroaryl, heteroatom connectedhydrocarbyl, heteroatom connected substituted hydrocarbyl, heteroatomconnected aryl, heteroatom connected heteroaryl, heteroatom connectedsubstituted aryl, heteroatom connected substituted heteroaryl, a groupof the formula C(O)R¹, a group of the formula —O—R¹, a group of theformula —NHR¹, a group of the formula —N(R¹)₂, a group of the formula—Sn(R¹)₃, and a group of the formula —Si(R¹)₃; wherein the R¹ and R²groups are independently selected from the group consisting of aryl,heteroaryl, hydrocarbyl, substituted aryl, substituted heteroaryl, andsubstituted hydrocarbyl; provided that said groups are bonded via acarbon atom; each R³ is independently selected from aryl; heteroaryl;hydrocarbyl; substituted aryl; substituted heteroaryl; substitutedhydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl;heteroatom connected substituted hydrocarbyl; heteroatom connectedheteroaryl; heteroatom connected substituted aryl; amino; halo; cyano;hydroxy; carboxy; a group of the formula —C(O)O—C—C₈ alkyl; a group ofthe formula —C(O)R¹; a group of the formula —O—R¹; a group of theformula —NHR¹; a group of the formula —N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈alkylthio; and oxo; or two R³ groups taken together can form a divalenthydrocarbyl, substituted hydrocarbyl, or be bonded directly to aheteroatom selected from oxygen, nitrogen, or sulfur; and n is from 0 to6.
 40. The intermediate of claim 39, wherein R¹ and R² are selected fromphenyl, trifluromethyl, and C₁-C₈ alkyl.
 41. The intermediate of claim39, wherein n is
 0. 42. The intermediate of claim 39, wherein R³ isfluoro.
 43. A process for forming a carbon-nitrogen bond, wherein saidcarbon is part of an aryl or heteroaryl ring, which comprises reactingan aryl or heteroaryl radical moiety with an azomethine moiety in thepresence of a hydrogen atom donor in an intramolecular reaction to forma fused ring system, wherein said azomethine moiety possesses at leastone radical stabilizing group, and the azomethine carbon is in theketone oxidation state or higher.
 44. The process of claim 43, whereinthe hydrogen atom donor is selected from the group consisting oforganostannane hydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, and selenols.
 45. The processof claim 44, wherein the organostannane is a compound of the Formula(X′)₃Sn—H, wherein, X′ is a group selected from C₁-C₆ alkyl, aryl, orflourous derivative thereof.
 46. The process of claim 45, wherein thecompound of the Formula (X)₃Sn—H is tri-n-butyltin hydride.
 47. Theprocess of claim 43, wherein the aryl radical moiety and azomethinemoiety are contained within a compound of the Formula

wherein each of the groups R⁴, R⁵, and R⁸ are independently selectedfrom hydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl;substituted heteroaryl; substituted hydrocarbyl; heteratom connectedaryl; heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula —C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, or two R⁸groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur; in addition, two R⁴ groups and/or two R⁵ groups canbe taken together represent oxo; R⁶ and R⁷ are independently selectedfrom aryl, heteroaryl, hydrocarbyl, substituted aryl, substitutedheteroaryl, and substituted hydrocarbyl; provided that said groups arebonded via a carbon atom; and n is from 0 to
 4. 48. The process of claim43, wherein the azomethine moiety is attached to a solid support.
 49. Aprocess for preparing compounds of the formula (R⁸)_(n)— (fused aryland/or heterocyclic ring)

 wherein each of the groups R⁴, R⁵, and R⁸ are independently selectedfrom hydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl;substituted heteroaryl; substituted hydrocarbyl; heteratom connectedaryl; heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, and/or twoR⁸ groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur; and n is from 0 to a number equivalent to availablesites on said fused aryl and/or heterocyclic ring;  in addition, two R⁴groups and/or two R⁵ groups can be taken together represent oxo;  R⁶ andR⁷ are independently selected from aryl, heteroaryl, hydrocarbyl,substituted aryl, substituted heteroaryl, and substituted hydrocarbyl;provided that said groups are bonded via a carbon atom;  and n is from 0to 4; which comprises contacting a compound of the formula (R⁸)_(n)—(fused aryl and/or heterocyclic ring)

wherein said fused aryl and/or heterocyclic ring possesses a carbonalpha to its point of attachment capable of forming an sp² hybridizedcarbon radical, said carbon substituted by a group Y, wherein Y is aradical leaving group; with a free radical initiator in the presence ofa hydrogen atom donor.
 50. The process of claim 49, wherein the hydrogenatom donor is selected from the group consisting of organostannanehydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, and selenols.
 51. The processof claim 50, wherein the organostannane is a compound of the Formula(X′)₃Sn—H, wherein X′ is a group selected from C₁-C₆ alkyl, aryl, orflourous derivative thereof.
 52. The process of claim 51, wherein thecompound of the Formula (X′)₃Sn—H is tri-n-butyltin hydride.
 53. Aprocess for preparing a compound of Formula (4)

wherein each of the groups R⁴, R⁵, and R⁸ are independently selectedfrom hydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl;substituted heteroaryl; substituted hydrocarbyl; heteratom connectedaryl; heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula —C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, or two R⁸groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur; in addition, two R⁴ groups and/or two R⁵ groups canbe taken together represent oxo; R⁶ and R⁷ are independently selectedfrom aryl, heteroaryl, hydrocarbyl, substituted aryl, substitutedheteroaryl, and substituted hydrocarbyl; provided that said groups arebonded via a carbon atom; and n is from 0 to 4; which comprisescontacting a compound of Formula (3)

with a free radical initiator in the presence of a hydrogen atom donor,wherein Y is a radical leaving group.
 54. The process of claim 53,wherein the hydrogen atom donor is selected from organostannanehydrides, organosilyl silanes, organogermanium hydrides,1,4-cyclohexadiene, γ-terpinene, thiols, and selenols.
 55. The processof claim 54, wherein the organostannane is a compound of the Formula(X′)₃Sn—H, wherein X′ is a group selected from C₁-C₆ alkyl, aryl, orflourous derivative therof.
 56. The process of claim 55, wherein thecompound of the Formula (X)₃Sn—H is tri-n-butyltin hydride.
 57. Theprocess of claim 53, wherein the free radical initiator is selected fromthe group consisting of azonitriles and peroxides
 58. The process ofclaim 57, wherein the free radical intitiator is comprised of 2,2′azobisisobutyronitrile.
 59. The process of claim 53, wherein R⁴ or F, iscarboxy, and wherein the compound of Formula (4) contains at least onechiral center.
 60. The process of claim 53, wherein the compound ofFormula (3) is attached to a solid support.
 61. A free radicalintermediate of the formula (R⁸)_(n)— (fused aryl and/or heterocyclicring)

 wherein said fused aryl and/or heterocyclic ring possesses an sp²hybridized carbon radical alpha to its point of attachment, and  whereineach of the groups R⁴, R⁵, and R⁸ are independently selected fromhydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl; substitutedheteroaryl; substituted hydrocarbyl; heteratom connected aryl;heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula —C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, or two R⁸groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur; and n is a number equivalent to available sites onsaid aryl and/or heterocyclic ring;  in addition, two R⁴ groups and/ortwo R⁵ groups can be taken together represent oxo;  R⁶ and R⁷ areindependently selected from aryl, heteroaryl, hydrocarbyl, substitutedaryl, substituted heteroaryl, and substituted hydrocarbyl; provided thatsaid groups are bonded via a carbon atom.
 62. A free radicalintermediate of the Formula

wherein each of the groups R⁴, R⁵, and R⁸ are independently selectedfrom hydrogen, aryl; heteroaryl; hydrocarbyl; substituted aryl;substituted heteroaryl; substituted hydrocarbyl; heteratom connectedaryl; heteroatom connected hydrocarbyl; heteroatom connected substitutedhydrocarbyl; heteroatom connected heteroaryl; heteroatom connectedsubstituted aryl; halo; amino; cyano; hydroxy; carboxy; a group of theformula —C(O)O—C₁-C₈ alkyl; a group of the formula —C(O)R¹; a group ofthe formula —O—R¹; a group of the formula —NHR¹; a group of the formula—N(R¹)₂; C₁-C₈ alkoxy; C₁-C₈ alkylthio; or two of R⁵ and R⁶, or two R⁸groups taken together can form a divalent hydrocarbyl, substitutedhydrocarbyl, or be bonded directly to a heteroatom selected from oxygen,nitrogen, or sulfur; in addition, two R⁴ groups and/or two R⁵ groups canbe taken together represent oxo; R⁶ and R⁷ are independently selectedfrom aryl, heteroaryl, hydrocarbyl, substituted aryl, substitutedheteroaryl, and substituted hydrocarbyl; provided that said groups arebonded via a carbon atom; and n is from 0 to
 4. 63. The intermediate ofclaim 62, wherein R⁶ and R⁷ are independently selected from C₁-C₈ alkyl,trifluormethyl, and phenyl.
 64. The process of claim 1, wherein theprocess is conducted on a substrate which is enantiomerically enriched.65. The process of claim 10, wherein the process is conducted on asubstrate which is enantiomerically enriched.
 66. The process of claim17, wherein the process is conducted on a substrate which isenantiomerically enriched.
 67. The process of claim 24, wherein theprocess is conducted on a substrate which is enantiomerically enriched.68. The process of claim 32, wherein the process is conducted on asubstrate which is enantiomerically enriched.
 69. The process of claim43, wherein the process is conducted on a substrate which isenantiomerically enriched.
 70. The process of claim 49, wherein theprocess is conducted on a substrate which is enantiomerically enriched.71. The process of claim 53, wherein the process is conducted on asubstrate which is enantiomerically enriched.